1. Field of the Invention
The present invention relates generally to the combinatorial synthesis of imidazol-pyrido-indole and imidazol-pyrido-benzothiophene derivatives. More specifically, the invention provides novel imidazol-pyrido-indole and imidazol-pyrido-benzothiophene derivatives as well as novel combinatorial libraries comprised of many such compounds, and methods of synthesizing the libraries.
2. Background Information
The process of discovering new therapeutically active compounds for a given indication involves the screening of all compounds from available compound collections. From the compounds tested one or more structure(s) is selected as a promising lead. A large number of related analogs are then synthesized in order to develop a structure-activity relationship and select one or more optimal compounds. With traditional one-at-a-time synthesis and biological testing of analogs, this optimization process is long and labor intensive. Adding significant numbers of new structures to the compound collections used in the initial screening step of the discovery and optimization process cannot be accomplished with traditional one-at-a-time synthesis methods, except over a time frame of months or even years. Faster methods are needed that allow for the preparation of up to thousands of related compounds in a matter of days or a few weeks. This need is particularly evident when it comes to synthesizing more complex compounds, such as the imidazol-pyrido-indole and imidazol-pyrido-benzothiophene compounds of the present invention.
Solid-phase techniques for the synthesis of peptides have been extensively developed and combinatorial libraries of peptides have been generated with great success. During the past four years there has been substantial development of chemically synthesized combinatorial libraries (SCLs) made up of peptides. The preparation and use of synthetic peptide combinatorial libraries has been described, for example, in U.S. Pat. Nos. 5,367,053 by Dooley, and 5,182,366 by Huebner, Appel et al. in WO PCT 92/09300, Geysen in published European Patent Application 0 138 855 and Pirrung in U.S. Pat. No. 5,143,854. Such SCLs provide the efficient synthesis of an extraordinary number of various peptides in such libraries and the rapid screening of the library which identifies lead pharmaceutical peptides.
Peptides have been, and remain, attractive targets for drug discovery. Their high affinities and specificities toward biological receptors as well as the ease with which large peptide libraries can be combinatorially synthesized make them attractive drug targets. The screening of peptide libraries has led to the identification of many biologically-active lead compounds. However, the therapeutic application of peptides is limited by their poor stability and bioavailability in vivo. Therefore, there is a need to synthesize and screen compounds which can maintain high affinity and specificity toward biological receptors but which have improved pharmacological properties relative to peptides.
Combinatorial approaches have recently been extended to "organic," or non-peptide, libraries. The organic libraries to the present, however, are of limited diversity and generally relate to peptidomimetic compounds; in other words, organic molecules that retain peptide chain pharmacophore groups similar to those present in the corresponding peptide. Although the present invention is principally derived from the synthesis of dipeptides, the dipeptides are substantially modified. In short, they are chemically modified through acylation and cyclization into the subject imidazol-pyrido-indoles and imidazol-pyrido-benzothiophenes, thus providing mixtures and individual compounds of substantial diversity.
The classical organic synthesis of variously substituted imidazol-pyrido-indoles is known. For example, as described in Konaoka et al., Tetrahedron, 24:2591 (1968), imidazol-pyrido-indoles can be obtained from the Bischler-Napieralski cyclization of tryptophan-containing derivatives. However, the current synthesis and study of imidazol-pyrido-indoles is a slow process. Each imidazole must be individually synthesized and separately tested. There exists a need to more efficiently synthesize and test various imidazol-pyrido-indole of substantial diversity.
Combinatorial technology has been used for the solid-phase synthesis of relatively small libraries of .beta.-carbolines. Such synthesis involves the condensation of a polymer bound tryptophan and an aldehyde or ketone component as described, for example, in Mayer et al., Tet. Lett., 37:5633 (1996), Yang and Guo, Tet. Lett., 37:5041 (1996) and Kaljuste and Unde'n, Tet. Lett., 36:9211 (1995). However, there remains a need to apply combinatorial technology to more complex molecules such as imidazol-pyrido-indoles, and to libraries of greater diversity.
This invention satisfies these needs and provides related advantages as well. The present invention overcomes the known limitations to classical organic synthesis of imidazol-pyrido-indoles as well as the shortcomings of combinatorial chemistry with small organics or peptidomimetics. Moreover, the present invention provides a large array of diverse imidazol-pyrido-indole which can be screened for biological activity, and as described below, are biologically active.